Process for producing 6, 7-bis (2-methoxyethoxy)-quinazolin-4-one

ABSTRACT

A process comprising a reaction of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acid compound in the presence of an ammonium carboxylate gives 6,7-bis(2-methoxyethoxy)quinazolin-4-one in a high yield.

FIELD OF THE INVENTION

The present invention relates to a process for preparation of6,7-bis(2-methoxyethoxy)quinazolin-4-one.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,747,498 discloses6,7-bis(2-methoxyethoxy)quinazolin-4-one as an intermediate in synthesisof 6,7-bis(2-methoxyethoxy)-4-(3-ethynylphenyl)-aminoquinazolinehydrochloride, which can be used as an anti-cancer drug.

Japanese Patent Provisional Publication No. 2002-293773 discloses aprocess comprising a reaction of ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate with ammonium formate toprepare 6,7-bis(2-methoxyethoxy)quinazolin-4-one. The publicationreports that the yield of the reaction was 80.5%.

DISCLOSURE OF THE INVENTION

Problems to be Solved by the invention

A primary object of the present invention is to provide a process forpreparing 6,7-bis(2-methoxyethoxy)-quinazolin-4-one in a high yield fromethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate.

Another object of the invention is to provide an industriallyadvantageous process for preparing6,7-bis(2-methoxyethoxy)quinazolin-4-one in a high yield using ethyl3,4-dihydroxybenzoate as a starting compound.

MEANS TO SOLVE THE PROBLEM

First, the present invention provides a process for preparation of6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises causing areaction of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formicacid compound in the presence of an ammonium carboxylate.

Second, the invention provides a process for preparation of6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps inorder of: causing a reaction of ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the presenceof a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of theethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acidcompound in the presence of an ammonium carboxylate to prepare6,7-bis(2-methoxyethoxy)quinazolin-4-one.

Third, the invention provides a process for preparation of6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps inorder of: causing a reaction of ethyl 3,4-bis(2-methoxyethoxy)benzoatewith nitric acid in the presence of sulfuric acid to prepare ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of theethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in thepresence of a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of theethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acidcompound in the presence of an ammonium carboxylate to prepare6,7-bis(2-methoxyethoxy)quinazolin-4-one.

Fourth, the invention provides a process for preparation of6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps inorder of: causing a reaction of ethyl 3,4-dihydroxybenzoate with2-chloroethyl methyl ether in an organic solvent in the presence of abase to prepare ethyl 3,4-bis(2-methoxyethoxy)benzoate; causing areaction of the ethyl 3,4-bis(2-methoxyethoxy)benzoate with nitric acidin the presence of sulfuric acid to prepare ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of theethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in thepresence of a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of theethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acidcompound in the presence of an ammonium carboxylate to prepare6,7-bis(2-methoxyethoxy)quinazolin-4-one.

The formulas of the compounds involved in the process of starting fromethyl 3,4-dihydroxybenzoate and yielding6,7-bis(2-methoxyethoxy)quinazolin-4-one are shown below.

Ethyl 3,4-dihydroxybenzoate is represented by the formula (1):

Ethyl 3,4-bis(2-methoxyethoxy)benzoate is represented by the formula(2):

Ethyl 4,5-bis (2-methoxyethoxy) -2-nitrobenzoate is represented by theformula (3):

Ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate is represented by theformula (4):

6, 7-Bis(2-methoxyethoxy)quinazolin-4-one is represented by the formula(5):

BEST MODE FOR CARRYING OUT THE INVENTION

The process for preparation of 6,7-bis(2-methoxyethoxy)quinazolin-4-oneaccording to the present invention is described below by referring tothe steps in order of:

causing a reaction of ethyl 3,4-dihydroxybenzoate with 2-chloroethylmethyl ether in an organic solvent in the presence of a base to prepareethyl 3,4-bis(2-methoxyethoxy)benzoate (first step);

causing a reaction of the ethyl 3,4-bis(2-methoxyethoxy)benzoate withnitric acid in the presence of sulfuric acid to prepare ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate (second step);

causing a reaction of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoatewith hydrogen in the presence of a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate (third step); and

causing a reaction of the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoatewith a formic acid compound in the presence of an ammonium carboxylateto prepare 6,7-bis(2-methoxyethoxy)quinazolin-4-one (fourth step).

(A) First Step

In the first step, ethyl 3,4-dihydroxybenzoate reacts with 2-chloroethylmethyl ether in an organic solvent in the presence of a base to prepareethyl 3,4-bis(2-methoxyethoxy)benzoate.

In the first step, the 2-chloroethyl methyl ether is used preferably inan amount of 1.0 to 20 moles, more preferably in an amount of 1.1 to 10moles, and most preferably in an amount of 1.1 to 5.0 mole based on onemole of ethyl 3,4-dihydroxybenzoate.

Examples of the bases used in the first step include: alkali metalhydroxides such as sodium hydroxide, potassium hydroxide; alkali metalcarbonates such as sodium carbonate and potassium carbonate; alkalimetal hydrogencarbonates such as sodium hydrogencarbonate and potassiumhydrogencarbonate; and alkali metal alkoxides such as sodium methoxideand potassium methoxide. The alkali metal hydroxides and the alkalimetal carbonates are preferred. The alkali metal carbonates are morepreferred. Most preferred is potassium carbonate. The base can be usedalone or in combination.

The base is used preferably in an amount of 1.0 to 20 moles, morepreferably in an amount of 1.1 to 10 moles, and most preferably in anamount of 1.1 to 5.0 moles based on one mole of ethyl3,4-dihydroxybenzoate.

There are no specific limitations with respect to the organic solventused in the first step, unless the organic solvent participates in thereaction. Examples of the organic solvents include: alcohols such asmethanol, ethanol, isopropanol and t-butanol; ketones such as acetone,methyl ethyl ketone and methyl isobutyl ketone; amides such asN,N-dimethylformamide and N-methyl-pyrrolidone; ureas such asN,N′-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide;nitriles such as acetonitrile and propionitrile; ethers such as diethylether, diisopropyl ether, tetrahydrofuran and dioxane; and aromatichydrocarbons such as toluene and xylene. The ketones, nitrites andamides are preferred. The organic solvent can be used alone or incombination.

The amount of the organic solvent is adjusted in consideration ofhomogeneity of the reaction solution and stirring conditions. Theorganic solvent is used preferably in an amount of 1 to 100 g, and morepreferably in an amount of 2 to 20 g based on 1 g of ethyl3,4-dihydroxybenzoate.

The first step can be carried out, for example, by mixing ethyl3,4-dihydroxybenzoate, 2-chloroethyl methyl ether, a base and an organicsolvent under stirring in an inert gas atmosphere. The reactiontemperature is preferably in the range of 20 to 200° C., and morepreferably in the range of 40 to 120° C. There are no specificlimitations with respect to the reaction pressure.

In the first step, ethyl 3,4-bis(2-methoxyethoxy)-benzoate is obtained.After the reaction is complete, ethyl 3,4-bis(2-methoxyethoxy)benzoatecan be isolated or purified for the second step. The isolation orpurification can be conducted according to the conventional method suchas filtration, concentration, distillation, recrystallization,crystallization, or column chromatography. Ethyl3,4-bis(2-methoxyethoxy)benzoate can also be used in the second stepwithout conducting isolation or purification. In the case that isolationor purification is not conducted, the solvent can be replaced in thesecond step.

(B) Second Step

In the second step, ethyl 3,4-bis(2-methoxyethoxy)-benzoate reacts withnitric acid in the presence of sulfuric acid to prepare ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.

In the second step, nitric acid is used preferably in an amount of 1.0to 50 moles, more preferably in an amount of 2.0 to 10 moles based onone mole of ethyl 3,4-bis(2-methoxyethoxy)benzoate. The nitric acid hasa concentration preferably in the range of 40 to 90 wt. %, and morepreferably in the range of 50 to 70 wt. %.

The second step is preferably carried out in the presence of a solvent.There are no specific limitations with respect to the solvent, unlessthe solvent participates in the reaction. Examples of the solventsinclude carboxylic acids such as formic acid, acetic acid, propionicacid and butyric acid. Acetic acid is preferred. The solvent can be usedalone or in combination.

The amount of the solvent is adjusted in consideration of homogeneity ofthe reaction solution and stirring conditions. The solvent is usedpreferably in an amount of 1 to 50 g, and more preferably in an amountof 1.1 to 20 g based on 1 g of ethyl 3,4-bis(2-methoxyethoxy)benzoate.

The second step can be carried out, for example by mixing ethyl3,4-bis(2-methoxyethoxy)benzoate, nitric acid, sulfuric acid and asolvent under stirring in an atmosphere of an inert gas. The reactiontemperature is preferably in the range of 20 to 90° C., more preferablyin the range of 30 to 80° C., and most preferably in the range of 45 to75° C. There are no specific limitations with respect to the reactionpressure.

In the second step, ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate isobtained. After the reaction is complete, ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate can be isolated or purified forthe third step. The isolation or purification can be conducted accordingto the conventional method such as filtration, concentration,distillation, recrystallization, crystallization, or columnchromatography. Ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate can alsobe used in the third step without conducting isolation or purification.In the case that isolation or purification is not conducted, the solventcan be replaced in the third step.

(C) Third Step

In the third step, ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate reactswith hydrogen in the presence of a metallic catalyst to prepare2-amino-4,5-bis(2-methoxyethoxy)benzoate.

The metallic catalyst used in the third step can contain at least onemetal atom selected from the group consisting of palladium, platinum andnickel. Examples of the metallic catalysts include palladium/carbon,palladium/barium sulfate, palladium hydroxide/carbon, platinum/carbon,platinum sulfide/carbon, palladium-platinum/carbon, platinum oxide andRaney nickel. Palladium/carbon, platinum/carbon, platinum sulfide/carbonand Raney nickel are preferred. The platinum/carbon catalyst isparticularly preferred. The metallic catalyst can be used alone or incombination.

In the third step, the metallic catalyst is used preferably in an amountof 0.1 to 1,000 mg in terms of metal atom amount, and more preferably inan amount of 0.5 to 500 mg based on 1 g of ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate. When the metallic catalystcomprises a metal carried on a carrier, the amount of the metal on thecarrier preferably is in the range of 1 to 2.9 wt. % based on amount ofthe carrier.

In the third step, hydrogen is used preferably in an amount of 3 to 50moles, and more preferably in an amount of 3 to 10 moles based on onemole of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.

The reaction in the third step is preferably carried out in the presenceof a solvent. There are no specific limitations with respect to thesolvent, unless the solvent participates in the reaction. Examples ofthe solvents include: water; alcohols such as methanol, ethanol,isopropanol, n-butanol, and t-butanol; carboxylic esters such as methylacetate, ethyl acetate, and methyl propionate; aromatic hydrocarbonssuch as benzene, toluene, xylene, and mesitylene; and ethers such asdiethyl ether, tetrahydrofuran, and dioxane. The alcohols and carboxylicesters are preferred, and methanol and ethanol are more preferred. Thesolvent can be used alone or in combination.

The amount of the solvent is adjusted in consideration of homogeneity ofthe reaction solution and stirring conditions. The solvent is usedpreferably in an amount of 1 to 100 g, and more preferably in an amountof 2 to 30 g based on 1 g of ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.

The reaction of the third step can be carried out, for example by mixingethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate, a metallic catalyst anda solvent under stirring in the presence of hydrogen gas (which can bediluted with an inert gas). The reaction temperature is preferably inthe range of 0 to 300° C., and more preferably in the range of 20 to200° C. The reaction pressure is preferably in the range of 0.1 to 10MPa, and more preferably in the range of 0.1 to 2 MPa.

After the reaction is complete, the final product, i.e., ethyl2-amino-4,5-bis(methoxyethoxy)benzoate, can be isolated or purified forthe fourth step. The isolation or purification can be conductedaccording to the conventional method such as filtration, concentration,distillation, recrystallization, crystallization, or columnchromatography. Ethyl 2-amino-4,5-bis(methoxyethoxy)benzoate can also beused in the fourth step without conducting the isolation orpurification. In the case that the isolation or purification is notconducted, the solvent can be replaced in the fourth step.

(D) Fourth Step

In the fourth step, ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoatereacts with a formic acid compound in the presence of an ammoniumcarboxylate to prepare 6,7-bis(2-methoxyethoxy)quinazolin-4-one.

Examples of the formic acid compounds include: formic acid; formicesters such as an ester of formic acid with a lower alcohol having 1 to6 carbon atoms (e.g., methyl formate and ethyl formate); and orthoformicesters such as an ester of orthoformic acid with a lower alcohol having1 to 6 carbon atoms (e.g., methyl orthoformate and ethyl orthoformate).Formic esters and orthoformic esters are preferred. More preferred areorthoformic esters. Most preferred are methyl orthoformate and ethylorthoformate.

In the fourth step, the formic acid compound is used preferably in anamount of 1.0 to 30 moles, and more preferably in an amount of 1.1 to 10moles based on one mole of ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate.

In the fourth step, an ammonium carboxylate is used. Examples of theammonium carboxylates include: ammonium aliphatic carboxylates such asan ammonium aliphatic carboxylate having 1 to 6 carbon atoms (e.g.,ammonium formate, ammonium acetate, and ammonium propionate); andammonium aromatic carboxylates such as an ammonium aromatic carboxylatehaving 7 to 12 carbon atoms (e.g., ammonium benzoate and ammoniumdichlorobenzoate). Ammonium aliphatic carboxylates are preferred. Morepreferred are ammonium formate and ammonium acetate. Most preferred isammonium acetate. The ammonium carboxylate can be used alone or incombination.

In the fourth step, the ammonium carboxylate is used preferably in anamount of 1.0 to 30 moles, and more preferably in an amount of 1.1 to 10moles based on one mole of 2-amino-4,5-bis(2-methoxyethoxy)benzoate.

The reaction in the fourth step can be carried out in the presence of asolvent. The reaction can also be carried out without a solvent. Thereare no specific limitations with respect to the solvent, unless thesolvent participates in the reaction. Examples of the solvents includealcohols such as methanol, ethanol, isopropanol, n-butanol, andt-butanol; amides such as N,N-dimethylformamide and N-methylpyrrolidone;ureas such as N,N′-dimethylimidazolidinone; sulfoxides such as dimethylsulfoxide; aromatic hydrocarbons such as benzene, toluene, xylene, andmesitylene; halogenated hydrocarbons such as methylene chloride,chloroform, and dichloroethane; nitriles such as acetonitrile, andpropionitrile; and ethers such as diethyl ether, tetrahydrofuran, anddioxane. The alcohols, amides and nitriles are preferred. More preferredare methanol, ethanol, N,N′-dimethylimidazolidinone and acetonitrile.The solvent can be used alone or in combination.

The amount of the solvent is adjusted in consideration of homogeneity ofthe reaction solution and stirring conditions. The solvent is usedpreferably in an amount of 0 to 50 g, more preferably in an amount of 0to 20 g, and most preferably in an amount of 0 to 5 g based on 1 g ofethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate.

The reaction in the fourth step can be carried out, for example, bymixing an ammonium carboxylate, ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate, a formic acid compound and asolvent under stirring in an inert gas atmosphere. The reactiontemperature is preferably in the range of 40 to 200° C., and morepreferably in the range of 50 to 150° C. There are no specificlimitations with respect to the reaction pressure.

After the reaction is complete, the final product, i.e.,6,7-bis(2-methoxyethoxy)quinazolin-4-one, can be isolated or purified.The isolation or purification can be conducted according to theconventional method such as filtration, concentration, distillation,recrystallization, crystallization, or column chromatography.

The present invention is further described by referring to the followingexamples.

EXAMPLES Synthesis Example 1 Synthesis of ethyl3,4-bis(2-methoxyethoxy)benzoate

In a 20 L-volume glass reaction vessel equipped with a stirrer, athermometer and a reflux condenser, 1,300 g (7.14 moles) of ethyl3,4-dihydroxybenzoate, 2,324 g (21.4 moles) of 2-chloroethyl methylether, 2,958 g (21.4 moles) of potassium carbonate and 6,500 mL ofN,N-dimethylformamide were placed. The mixture was allowed to react witheach other at 90 to 100° C. for 9 hours while stirring. After thereaction was complete, the reaction solution was cooled to roomtemperature. The reaction solution was then filtered, and washed with6,500 mL of acetone. The filtrate was concentrated, 3,900 mL of ethylacetate and 3,900 mL of a saturated aqueous sodium carbonate solutionwere added to the concentrate. The separated organic layer (ethylacetate layer) was washed twice with 3,900 mL of a saturated aqueoussodium chloride solution to obtain a solution mixture containing ethyl3,4-bis(2-methoxyethoxy)benzoate. The solution mixture was analyzed(according to an absolute quantitative method) by a high performanceliquid chromatography. It was confirmed that 2,023 g of ethyl3,4-bis(2-methoxyethoxy)benzoate was produced (reaction yield: 95%).After 3,939 mL of acetic acid was added to the solution mixture, themixture was concentrated under reduced pressure to distill ethyl acetateoff. Thus, an acetic acid solution of ethyl3,4-bis(2-methoxyethoxy)benzoate was obtained.

Synthesis Example 2 Synthesis of ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate

In a 20 L-volume glass reaction vessel equipped with a stirrer, athermometer and a reflux condenser, the acetic acid solution containing2,023 g (6.78 moles) of ethyl 3,4-bis(2-methoxyethoxy)benzoate preparedin the Synthesis Example 1 was placed. To the solution, 318 g (3.18moles) of concentrated sulfuric acid was gently added while stirring thesolution at room temperature. The mixture was heated to 60 to 70° C. Tothe mixture, 1,857 g (20.34 moles) of 69 wt. % nitric acid was gentlyadded while stirring the mixture. The resulting mixture was allowed toreact for 2 hours while maintaining the temperature. After the reactionwas complete, the reaction solution was cooled to room temperature. Tothe reaction solution, 5,200 mL of a 20 wt. % aqueous sodium chloridesolution and 5,200 mL of toluene were added. The separated organic layer(toluene layer) was washed twice with 7,800 mL of a 1 mole per L aqueoussodium hydroxide solution, and further washed twice with 7,800 mL of a20 wt. % aqueous sodium chloride solution. The organic layer wasconcentrated under reduced pressure to obtain 2,328 g of ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an orange liquid (isolationyield: 100%).

Synthesis Example 3 Synthesis of ethyl2-amino-4,5-bis(2-methoxyethoxy)-benzoate

In a 20 L-volume glass reaction vessel equipped with a stirrer, athermometer and a reflux condenser, 2,328 g (6.78 moles) of the ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate prepared in the SynthesisExample 2, 2 wt. % platinum per 118 g of carbon (50 wt.% product, N. E.Chemcat Corporation, 6.0 mmoles in terms of platinum metallic atom) and9,440 mL of methanol were placed. The mixture was allowed to react at 50to 60° C. for 6 hours in an atmosphere of hydrogen while stirring. Afterthe reaction was complete, the reaction solution was cooled to roomtemperature, and filtered. The filtrate was concentrated under reducedpressure to obtain 1,960 g of ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate as an orange liquid (isolationyield: 92%).

Synthesis Example 4 Synthesis of6,7-bis(2-methoxyethoxy)quinazolin-4-one

In a 20 L-volume glass reaction vessel equipped with a stirrer, athermometer and a reflux condenser, 1,600 g (5.11 moles) of the ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate prepared in the SynthesisExample 3, 1,626 g (15.3 moles) of methyl orthoformate, 1,181 g (15.3moles) of ammonium acetate and 4,800 mL of methanol were placed. Themixture was allowed to react under refluxing conditions (60 to 70° C.)for 7 hours while stirring. After the reaction was complete, thereaction solution was cooled to 60° C. To the reaction solution, 4,800mL of methanol was added. The mixture was stirred for 30 minutes whilemaintaining the temperature, cooled to 0 to 5° C., and further stirredfor 1 hour. The resulting mixture was filtered to obtain 1,373 g of6,7-bis(2-methoxyethoxy)quinazolin-4-one as white crystals (isolationyield: 91%).

The total yield based on ethyl 3,4-dihydroxybenzoate was 80%.

1. A process for preparation of6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises causing areaction of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formicacid compound in the presence of an ammonium carboxylate.
 2. A processfor preparation of 6,7-bis(2-methoxyethoxy)quinazolin-4-one, whichcomprises the steps in order of: causing a reaction of ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the presenceof a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of theethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acidcompound in the presence of an ammonium carboxylate to prepare6,7-bis(2-methoxyethoxy)-quinazolin-4-one.
 3. A process for preparationof 6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the stepsin order of: causing a reaction of ethyl3,4-bis(2-methoxyethoxy)benzoate with nitric acid in the presence ofsulfuric acid to prepare ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate;causing a reaction of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoatewith hydrogen in the presence of a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of theethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acidcompound in the presence of an ammonium carboxylate to prepare6,7-bis(2-methoxyethoxy)-quinazolin-4-one.
 4. A process for preparationof 6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the stepsin order of: causing a reaction of ethyl 3,4-dihydroxybenzoate with2-chloroethyl methyl ether in an organic solvent in the presence of abase to prepare ethyl 3,4-bis(2-methoxyethoxy)benzoate; causing areaction of the ethyl 3,4-bis(2-methoxyethoxy)benzoate with nitric acidin the presence of sulfuric acid to prepare ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of theethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in thepresence of a metallic catalyst to prepare ethyl2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of theethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acidcompound in the presence of an ammonium carboxylate to prepare6,7-bis(2-methoxyethoxy)quinazolin-4-one.
 5. The process according toone of the claims 1 to 4, wherein the formic acid compound is anorthoformic ester.
 6. The process according to one of the claims 1 to 4,wherein the ammonium carbonate is ammonium acetate.
 7. The processaccording to the claim 3 or 4, wherein the reaction of ethyl3,4-bis(2-methoxyethoxy)-benzoate with nitric acid in the presence ofsulfuric acid is conducted at a temperature in the range of 45 to 75° C.to prepare ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.
 8. Theprocess according to the claim 3 or 4, wherein the metallic catalystcomprises 1 to 2.9 wt. % of platinum carried on a carbon carrier.